PROJECT SUMMARY/ABSTRACT Through Phase I and II SBIR NCI support, Omniox has developed a breakthrough oxygen carrying protein, OMX-4.80, that delivers oxygen to tumors and greatly reduces hypoxia. This Phase IIB proposal describes IND-enabling studies and Phase 1b clinical trials in certain cancers, with the potential to expand to a range of other hypoxic solid cancers, to enhance radiation therapy (RT). Backed by leaders in the field of tumor hypoxia and RT, and led by experts in protein-based oxygen carriers and oncology drug development, Omniox is focused on translating promising preclinical data of OMX-4.80 into patients. Omniox has received commitments from high net worth investors and venture capital groups to match NCI funding for ~$1million per year for three years; the initial series A termsheet describes a $1million funding commitment that is conditional on the funding of this proposal. Hypoxia, a common feature of solid tumors, is considered a major obstacle for the clinical management of cancer by radiation therapy (radiotherapy, RT). Oxygen is required by ionizing radiation to damage DNA and kill cancer cells. Cancer patients with significantly hypoxic tumors tend to have a poor prognosis for survival. Given the clinical relevance of hypoxia, a long-time objective in the field of RT has been to effectively radiosensitize solid tumors by attenuating or exploiting this pathophysiological state. The heme-nitric oxide/oxygen-binding (H-NOX) proteins were initially discovered at the University of California, Berkeley and are exclusively licensed to Omniox for therapeutic development. H-NOX are neutral towards nitric oxide (NO), comparing favorably with the high NO reactivity and hypertensive properties of hemoglobin-based oxygen carriers; can be tuned to achieve specific oxygen affinities; are structurally stable above 80 C, and chemically stable for weeks at room temperature; and can be surface-modified to alter size, oncotic properties, or tissue targeting. Preclinical data on the lead H-NOX, OMX-4.80, established that it demonstrates clinically relevant tumor biodistribution after IV administration, and significantly reduces hypoxia over multiple hours. Additionally, in orthotopic tumor models, the lead candidate generated a significant reduction in tumor growth and an extension in overall survival when coupled with RT. Finally, in toxicity testing, the H-NOX protein demonstrated a strong safety profile, without any of the significant safety or toxicity concerns that have plagued other tumor oxygenation technologies. This Phase IIB proposal has been prepared in accordance with guidelines for developing radiation enhancement therapies (DIRM report) as published by the NCIs Radiation Modifier Working Group and describes the continued preclinical research, safety testing, and clinical development through Phase 1 trials. Successful completion of this study should result in significant investor interest in supporting further clinical development.